This grant seeks a biophysical understanding of tissue morphology: how do we explain the characteristic shapes and levels of organization of cellular tissues? Genetics and cell biology have obtained much information about the biomolecules that are important in regulating morphology. However, the link between molecular activities on the subcellular (nm) scale and morphology on the tissue scale (mm) has not been made. To establish such a connection, the grant draws on the abilities of an interdisciplinary research team, combining the cell biology and genetic expertise of the group of Richard Carthew (Northwestern University) with expertise in the physics and theoretical mechanics of soft materials from Sascha Hilgenfeldt's group (University of Illinois). The main objective of the project is the mathematical modeling of epithelial tissue mechanics. In published results, the team found cells in the Drosophila eye epithelium adopt shapes and neighbor relations that achieve passive energy minimization. Forces along the plane of cell membranes become balanced, leading to a mechanical equilibrium. Important contributing forces are those due to intercellular adhesion and actin cortical contraction. We propose that force imbalances naturally lead to a moving tissue system in which the changes in cell contacts and shapes result in the tissue reaching stasis with a local energy minimum. We aim to test this hypothesis by engineering force imbalances in certain cells and describing the static end-result. If correct, the mathematical model will accurately predict the mechanical outcomes of such experiments. Extending the hypothesis further, one might consider that morphogenesis is a progressive series of local energy minima reached in response to force change. We aim to test this hypothesis with a mathematical model that describes a very defined mechanical pathway in the eye, where four cells change contact with each other. Will the model predict the mechanical features and ways in which adhesive and contractive forces change over time and location? Lastly, we know that other forces exist within tissues but do not understand their relative contributions to tissue mechanics. To achieve this, we will develop a mathematical model that also considers cellular viscoelasticity, fluid pressure, matrix adhesion, and organelle displacement. The model will assume that these forces balance in three dimensions, leading to a passive energy minimization. Understanding the biophysical nature of tissue morphology will have great benefit for regenerative medicine and tissue engineering.